Background: Hepatocellular carcinoma (HCC) is considered as the primary malignancy of the liver that usually occurs on top of chronic viral hepatitis. The TP53 (tumor protein 53) is a tumor suppressor gene which is the key in tumor development and progression and the single nucleotide polymorphism (SNP) of the p53 gene codon 72 (p53Arg/Pro) changes the structure of the protein. Objectives: to determine the association of the TP53 Arg72Pro polymorphism with the risk of HCC development in Hepatitis C virus (HCV) infected Egyptian patients. Methodology: This is a case control study conducted in Sohag University Hospital on 100 participants (20 HCC, 20 CHCV, 40 LC and 20 control). TP53 gene polymorphism was identified by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP), serum level of TP53 was measured by quantitative ELISA. Results: The GG genotype / G allele has the highest frequency in the controls, while the CC genotype/ C allele was more frequently found in the HCC patients. Carriage of TP53 CC genotype and TP53 serum level have a statistical significant association with HCC development. Conclusion: the CC genotype and the Pro (C) allele of TP53, codon 72 are risk factors for HCC in patients infected with HCV and the serum TP53 level is overexpressed in HCC patients.